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CN105683180A - Nmda antagonist prodrugs - Google Patents

Nmda antagonist prodrugs Download PDF

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Publication number
CN105683180A
CN105683180A CN201480060416.0A CN201480060416A CN105683180A CN 105683180 A CN105683180 A CN 105683180A CN 201480060416 A CN201480060416 A CN 201480060416A CN 105683180 A CN105683180 A CN 105683180A
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Prior art keywords
base
phenyl
pyridine
compound
ethyl
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CN105683180B (en
Inventor
G·诺德瓦尔
K·豪格丁
P·J·马姆博格
A·谢尔斯
D·魏格尔特
P·伯恩斯坦
M·夸克
B·迈克尔
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AstraZeneca AB
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AstraZeneca AB
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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Abstract

Prodrugs of the NMDA antagonist (S) -1-phenyl-2- (pyridin-2-yl) ethylamine are provided for use in the treatment of depression (particularly major depressive disorder) or pain; compositions containing them and processes for their preparation.

Description

Nmda antagonist prodrug
This application claims the priority of the U.S. Provisional Patent Application 61/899,903 that on November 5th, 2013 submits to, its full content is incorporated herein by the mode introduced.
The present invention relates to the prodrug of nmda antagonist (S)-1-phenyl-2-(pyridine-2-base) ethamine and treating depression and depressive disorders (especially major depressive disorder (MDD)) and be used for treating the purposes in pain (such as neuropathic pain). (S) prodrug of-1-phenyl-2-(pyridine-2-base) ethamine can be used for treating that Rett syndrome, suicidal idea, bipolar disorder (including bipolar depression), obsessive compulsive disorder, Schain poison gas be poisoning and status epilepticus. The invention still further relates to pharmaceutical composition of comprising described prodrug and preparation method thereof.
Various forms of pain are ubiquitous in people lives. Pain and postoperative pain from damage are often provisional but it also may be very serious and lasting. Neuropathic pain such as diabetic neuropathy and postherpetic neuralgia have a strong impact on patient. Every year, there is the patient that up to ten million people includes being in end of life to bear pain in the world, and lack enough treatments.
Depression affects about 100,000,000 2,000 ten thousand people in the world. The symptom of depression include but not limited to the forfeiture of hypothymergasia, interest or enjoyment, guilty-feeling or self-value reduce, sleep or appetite disorder, deficient in energy and absent minded, or any of the above described combination. These problems can be long-term or recurrent and may result in the individual ability looking after himself daily responsibility and be subject to extensive damage. Measured by YearsLivedwithaDisability (YLD), depression is disabled main cause and in 2000, by DisabilityAdjustedLifeYears (DALY; Time of the potential human loss namely caused due to premature death and the summation in the effectively time that life is lost caused due to Disability) measured by, depression is the 4th principal element of global disease burden. To the year two thousand twenty, it is contemplated that depression will become for whole ages, the second place of DALY ranking that calculates in both masculinity and femininities. At present, depression become age of two kinds of sexes for mixing 15-44 year classification in second inducement of DALY.
(S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride is had been disclosed, it is used for treating MDD (GerardSanacora et al. through venoclysis treatment, December in 2012 6 days is at AnnualMeetingoftheAmericanCollegeofNeuropsychopharmacolo gy, Hollywood, the poster that Florida, USA show). Other are correlated with and openly include WO1993/020052, WO2000/056324 and WO2000/63175. For convenience, it is possible to be significant using this medicine as oral dosage form. But, problem about this peroral dosage form of (S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride will be that it may result in intravenous abuse, such as, the peroral dosage form making (S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride fragmentates, and immediately injects (S)-1-phenyl-2-(pyridine-2-base) the ethylamine dihydrochloride peroral dosage form of the pulverizing obtained.The prodrug of prediction (S)-1-phenyl-2-(pyridine-2-base) ethamine decomposes to provide (S)-1-phenyl-2-(pyridine-2-base) ethamine in human organism, thus, when the prodrug of (S)-1-phenyl-2-(pyridine-2-base) ethamine is orally administered to, it will decompose to discharge (S)-1-phenyl-2-(pyridine-2-base) ethamine of the upper effective dose for the treatment of. If but intravenous gives the prodrug of the present invention, the intravenous of (S)-1-phenyl-2-(pyridine-2-base) ethamine comparing corresponding dosage gives, predict that this prodrug will discharge (S)-1-phenyl-2-(pyridine-2-base) ethamine with slower speed, and then provide relatively low Cmax. The use of prediction (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug will improve clinical safety distribution (such as under overdose or drug dependence (such as tablet disintegrating) situation) of (S)-1-phenyl-2-(pyridine-2-base) ethamine. Therefore, in a word, (S)-1-phenyl-2-(pyridine-2-base) the direct posting port formulation of ethamine will be caused abuse. Compare during the metabolism in vivo of the compound of the present invention and obtain (S)-1-phenyl-2-(pyridine-2-base) ethamine with slower speed when intravenous gives (S)-1-phenyl-2-(pyridine-2-base) ethamine, and therefore will not result in the probability of (S)-1-phenyl-2-(pyridine-2-base) ethamine abuse.
Accompanying drawing explanation
Fig. 1 a and 1b elaborates to hatch in people's intestinal juice in process the prodrug (embodiment 5) of (S)-1-phenyl-2-(pyridine-2-base) ethamine to the conversion of (S)-1-phenyl-2-(pyridine-2-base) ethamine. Specifically, Fig. 1 a elaborates when hatching in process in people's intestinal juice changes into (S)-1-phenyl-2-(pyridine-2-base) ethamine, prodrug (embodiment 5) concentration (initial concentrations of 30,100,300 and 600 μMs) of (S)-1-phenyl-2-(pyridine-2-base) ethamine. Fig. 1 b describes hatches in process in people's intestinal juice, (S)-1-phenyl-2-(pyridine-2-base) ethamine concentration (initial concentrations that embodiment is 5,30,100,300 and 600 μMs) when from (S)-1-phenyl-2-(pyridine-2-base) ethamine pro-drug conversion.
Summary of the invention
The invention provides the compound or pharmaceutically acceptable salt thereof of formula (I)
Wherein R1 is C1-6Alkyl C (O) O (C1-6Alkoxyl), or
AA is the natural amino acid that peptide bond connects.
Alkyl is straight or branched and comprises 1-6 such as 1-4 carbon atom. Alkyl is such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group.
Alkoxyl is straight or branched and comprises 1-6 such as 1-4 carbon atom. Alkoxyl is such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
Detailed description of the invention
One aspect of the present invention provides the compound of formula (I), and wherein R1 is C1-6Alkyl C (O) O (C1-6Alkoxyl), for instance it is C1-4Alkyl C (O) O (C1-4Alkoxyl). Example includes: (CH3)2CHC(O)OCH2O、(CH3)2CHC(O)OCH(CH(CH3)2)O、CH3C(O)OCH(CH3) O or (CH3)2CHC(O)OCH(CH3)O。
On the other hand, the present invention provides the compound of formula (I), and wherein R1 is
And AA is the natural amino acid that peptide bond connects.
On the other hand, the present invention provides the compound of formula (I), and wherein R1 is
(therefore chiral centre * has S absolute configuration).
On the other hand, the present invention provides the compound of formula (I), and wherein AA is such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, aspartic acid, glutamic acid, agedoite, glutamine, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline or hydroxyproline. On the other hand, AA is selected from: tyrosine, tryptophan, phenylalanine, leucine, arginine, histidine, lysine and valine.On the other hand, AA is selected from: tyrosine, arginine, histidine, lysine and valine. On the other hand, AA is valine.
Suitable pharmaceutical salts is such as acid-addition salts, example hydrochloric acid salt, hydrobromate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalates, mesylate, tosilate, disulfate, benzene sulfonate, esilate, malonate, xinafoate, Ascorbate, oleate, nicotinate, saccharin hydrochlorate, adipate, formates, oxyacetate, Pfansteihl salt, D-lactate, aspartate, malate, L-TARTARIC ACID salt, D-tartrate, stearate, 2-furoate, 3-furoate, napadisilate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanedisulphonate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), 2-sym-toluenesulfonic acid salt, 2-naphthalene sulfonate, D-mandelate, L-mandelate, 2,5-dichloro benzosulfonic acid salt, cinnamate or benzoate.
The compound of formula (I), it is:
Isopropylformic acid. (S)-(1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) methyl ester;
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester;
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester diastereomer 1;
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester diastereomer 2;
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester;
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 1;
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 2;
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester;
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 1;
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 2;
(S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
(S)-1-((S)-2,6-diaminourea caproyl)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
(S)-1-((S)-2-amino-3-(1H-imidazol-4 yl) propiono)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
2-((S)-2-((S)-1-((S)-2-amino-3-(4-hydroxy phenyl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine;
2-((S)-2-((S)-1-((S)-2-amino-3-(1H-indol-3-yl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine;
(S)-1-((S)-2-amino-3-PHENYLPROPIONYL)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide; Or
(S)-1-((S)-2-amino-4-methylvaleryl)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
Or the pharmaceutical salts of any of the above-described person.
The compound of the present invention can be prepared by the proper method described in this area or by the proper method described in embodiment. Such as compound (S)-1-phenyl-2-(pyridine-2-base) ethamine can be prepared by the methodology in EP-0633879, and the content of this document is incorporated to by the mode introduced.
The compound of the present invention, wherein R1 is
It can use by being chemically synthesized that 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridine intermediate carries out.
Therefore, another fermentation, the present invention provides compound 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridine or its salt:
Wherein said salt is such as hydrochlorate, hydrobromate, sulfate, phosphate, acetate, mesylate, tosilate, formates or benzoate.
On the other hand, the present invention provides midbody compound 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridinium chloride
The compound or pharmaceutically acceptable salt thereof of formula (I) can be used for treating depression (such as major depressive disorder, for instance the major depressive disorder that treatment is obstinate).
The compound or pharmaceutically acceptable salt thereof of formula (I) can be used for treating pain (such as neuropathic pain, chronic pain, phantom pain, nociceptive pain, psychogenic pain, accident pain or breakthrough pain).
The compound or pharmaceutically acceptable salt thereof of formula (I) can be used for treating that Rett syndrome, suicidal idea, bipolar disorder, obsessive compulsive disorder, Schain poison gas be poisoning or status epilepticus.
Therefore, the present invention provides the compound or pharmaceutically acceptable salt thereof of the formula (I) for treating as defined herein. Therefore, term as used herein " prodrug " can refer to the compound of the formula (I) of salt form or free alkali form.
On the other hand, the present invention provides the compound or pharmaceutically acceptable salt thereof of formula (I) to be as defined herein used for the purposes in the medicine treated in preparation.
On the other hand, the present invention provides and gives the method to patient by (S)-1-phenyl-2-(pyridine-2-base) ethamine, described method includes being given by the compound or pharmaceutically acceptable salt thereof of formula (I) to patient, the compound of wherein said formula (I) in described patient metabolism to produce (S)-1-phenyl-2-(pyridine-2-base) ethamine.
In the context of the present specification, unless there are specific contrary instruction, otherwise term " treatment " also includes " prevention ". Term " treatment " and " treatment ground " also should correspondingly be explained.
The treatment of prevention expection and the antecedent attacks suffering from discussed disease or disease or the people that is considered in the risk of discussed disease or the disease increased in other words is especially relevant. The people being in the risk of development specified disease or disease generally comprises the family history with described disease or disease or has passed through this gene test or screening discriminating for those people developing described disease or the special susceptible of disease.
The present invention furthermore provides the method for the treatment of depression, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as defined herein of therapeutically effective amount.
The present invention furthermore provides the method for the treatment of MDD, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as defined herein of therapeutically effective amount.
The present invention furthermore provides the method for the treatment of pain, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as defined herein of therapeutically effective amount.
The present invention furthermore provides the method for the treatment of neuropathic pain, chronic pain, phantom pain, nociceptive pain, psychogenic pain, accident pain or breakthrough pain, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as defined herein of therapeutically effective amount.
The compound or pharmaceutically acceptable salt thereof of formula (I) is for treating the purposes of depression.
The compound or pharmaceutically acceptable salt thereof of formula (I) is for treating the purposes of pain.
For above-mentioned therapeutic use, the dosage given changes inevitable with the compound adopted, mode of administration, intended treatment and the disease specified. Such as, if inhalation, then every daily dose of the compounds of this invention can be every kg body weight 0.05 microgram (μ g/kg) extremely every kg body weight 100 microgram (μ g/kg). Alternatively, if compound is orally administered to, then every daily dose of the compounds of this invention can be every kg body weight 0.01 microgram (μ g/kg) extremely every kg body weight 100 microgram (μ g/kg).
Compound and the pharmaceutical salts thereof of formula (I) can be used alone, but generally the form with pharmaceutical composition given, and the compound/salt (active component) of its Chinese style (I) combines with pharmaceutic adjuvant, diluent or carrier. For selecting and preparing the conventional method of suitable pharmaceutical preparation as example " Pharmaceuticals-TheScienceofDosageFormDesigns ", M.E.Aulton, ChurchillLivingstone, described in 1988.
Depend on giving pattern, described pharmaceutical composition preferably comprises the active component of following percentage ratio: 0.05-99%w (percentage by weight), more preferably 0.05-80%w, even more preferably from 0.10-70%w and even more preferably from 0.10-50%w, all weight percents is based on all compositions meter. In some embodiments, described pharmaceutical composition comprises the active component of 0.5%w. In some embodiments, described pharmaceutical composition comprises the active component of 20%w.
The present invention also provides for pharmaceutical composition, and it comprises and the compound or pharmaceutically acceptable salt thereof of pharmaceutic adjuvant, the formula (I) as defined herein of diluent or carrier combination.
The method that the present invention further provides pharmaceutical composition for preparing the present invention, it includes mixing the compound or pharmaceutically acceptable salt thereof of formula (I) as defined herein with pharmaceutic adjuvant, diluent or carrier.
For oral administration, the compound of the present invention can mix with following adjuvant or carrier: such as lactose, sucrose, sorbitol, mannitol; Starch is potato starch, corn starch or amylopectin such as; Cellulose derivative; Binding agent such as gelatin or polyvinylpyrrolidone; And/or lubricant such as magnesium stearate, calcium stearate, Polyethylene Glycol, wax, paraffin etc., it is pressed into tablet subsequently. If needing coated tablet, the sugar juice coating of concentration can be used in the core prepared as described above, and described sugar juice comprises such as arabic gum, gelatin, Talcum and titanium dioxide. Alternatively, described tablet can with the suitable polymer coating being dissolved in volatile organic solvent.
For the preparation of Perle, the compound of the present invention can mix with such as vegetable oil or Polyethylene Glycol. Hard gelatin capsule can comprise the granule of the compound using the above-mentioned excipient for tablet. Additionally, the liquid of the compounds of this invention or semi-solid preparation can be filled in hard gelatin capsule.
The compound of the present invention also can give for the compound combination treating above-mentioned disease with other.
The following example has illustrated the present invention. In an embodiment, employ some technology and shall now be described.
Anti-phase (RP) post carries out high performance liquid chromatography (HPLC). Adopt linear gradient, it uses such as mobile phase A (0.1% formic acid in MilliQH2O or 10mMNH4OAc and the 5%CH3CN in 0.1%NH3 or MilliQH2O in MilliQH2O, or 0.05% trifluoroacetic acid in MilliQH2O, or the NH4HCO3 (10mM) in MilliQH2O) and B (CH3OH or CH3CN).Cation and/or ion mode use electron spray ionisation (ESI+/-), atmospheric pressure photoionization (APPI+/-) and/or Atmosphere Pressure Chemical Ionization (APCI) (APCI+/-) implement mass spectrum (MS) and analyze.
The GC being equipped with mass spectrograph (MS) or flame ionization detector (FID) implements gas chromatography (GC). MS ion source is electron collision (EI) or chemi-ionization (CI, reacting gas: methane). For separating, use capillary column, for instance DB-5MS (J&WScientific). Have employed linear temperature gradient.
Normal phase column implements supercritical fluid chromatography (SFC). Adopt constant gradient stream, use mobile phase A (CO2) and such as Mobile phase B (MeOH, EtOH or IPA).
Alternatively, normal phase column implements high performance liquid chromatography (HPLC). Adopt linear gradient or constant gradient stream, use such as mobile phase A (heptane) and B (EtOH or IPA).
Equipped with record H NMR spectroscopy on 300MHz (or the more High-Field) NMR spectrometer of appropriately configured probe. Unless otherwise indicated, compose at ambient temperature record. To provide chemical shift from the low field of ppm of TMS (0.00ppm) and High-Field. Use following contrast signal: TMS δ 0.00 or following residual solvent signal: DMSO-d6 δ 2.49, CD3OD δ 3.30, acetone-d62.04, CDCl3 δ 7.25 or D2O δ 4.79 (unless otherwise indicated). Resonance multiplicity is referred to as s, d, t, q, m, br and app respectively for unimodal, bimodal, triplet, quartet, multiplet, broad peak and obvious peak.
Abbreviated list
DBU1,8-diazabicylo [5.4.0] 11 carbon-7-alkene
DCM dichloromethane
DEA diethylamine
DIPEA diisopropyl ethyl amine
DMF dimethylformamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
HATU2-(1H-7-azepine benzo triazol-1-yl)--1,1,3,3-tetramethylurea hexafluorophosphate
IPA isopropanol
MTBE methyl tertiary butyl ether(MTBE)
Rt room temperature or ambient temperature, about 20-25 DEG C
Sat is saturated
T3P propane phosphonic acid acid anhydride
Embodiment 1
Isopropylformic acid. (S)-(1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) methyl ester
Step A
Isopropylformic acid. chloromethyl ester
By sodium bicarbonate (2092mg, 24.91mmol), 4-butyl ammonium hydrogen sulfate (220mg, 0.65mmol) it is added in the isopropylformic acid. (0.600mL, 6.47mmol) solution in DCM (6mL) with water (6mL). With quickly stirring, add chlorosulfonic acid chloromethyl ester (0.767mL, 7.44mmol) at rt and reactant mixture is stirred overnight at rt subsequently. Subsequently with DCM (10mL) diluted reaction mixture, wash (2x10mL) with water, through Na2SO4Dry, filter and concentration obtains isopropylformic acid. chloromethyl ester (746mg, 84%), use it for next step without being further purified.
1HNMR(500MHz,CDCl3)δppm1.17(m,6H),2.62(m,1H),5.72(s,2H).
Step B
Isopropylformic acid. (S)-(1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) methyl ester
In room temperature by cesium carbonate (1543mg, 4.74mmol) with tetrabutylammonium iodide (1749mg, 4.74mmol) it is added in (S)-1-phenyl-2-(pyridine-2-base) ethamine (313mg, 1.58mmol) solution in dry DMF (8mL). Make carbon dioxide bubbling pass through reactant mixture 30 minutes, add the isopropylformic acid. chloromethyl ester (647mg, 4.74mmol) solution in DMF (2mL) subsequently. At rt by lasting CO2Gas sparging stirred overnight reactant mixture continuously stirred weekend excessively are without adding CO further2Gas. Dilute with water reactant mixture also extracts with EtOAc (3x), and the organic layer merged with water (2x), salt water washing, through Na2SO4Dry and concentrate.Complete purification by column chromatography (using the EtOAc gradient (0-60%) in heptane) and obtain title compound (239mg, 44.2%).
1HNMR (500MHz, DMSO-d6) δ ppm1.00 (m, 6H), 2.46 (m, 1H, is partly hidden in DMSO-d6), 3.09 (m, 2H), 5.04 (m, 1H), 5.52 (m, 2H), 7.17-7.24 (m, 3H), 7.27-7.34 (m, 4H), 7.65 (td, 1H), 8.24 (d, 1H), 8.49 (m, 1H).
Embodiment 2
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester
Owing to there being configuration two kinds possible at the carbon atom place represented with *, there is diastereomer two kinds different in embodiment 2. It is called embodiment 2 diastereomer 1 and embodiment 2 diastereomer 2. Do not determine its absolute configuration.
Step A
Isopropylformic acid. 2-methyl isophthalic acid-((4-(methyl sulphonyl) phenoxy group) ketonic oxygen base) propyl ester.
I 4-(methyl mercapto) phenol (8.46g, 57.30mmol) is absorbed in DCM (60mL) by (), and subsequently reaction flask is cooled to 0 DEG C. Add chloro-carbonic acid 1-chloro-2-methyl propyl ester (4.27mL, 28.65mmol) subsequently. Last, at 0 DEG C, the mixture 5 minutes being added dropwise over the 4-methyl morpholine (7.87mL, 71.63mmol) solution in DCM (40mL) for 50 minutes and obtaining in the stirring of this temperature, and final stir 150 minutes at rt. Wash reactant mixture (2x) with water, through Na2SO4Dry, filter and evaporation obtains carbonic acid 1-chloro-2-methyl propyl ester 4-(methylsulfany) phenyl ester (13.84g), use it for next step without being further purified.
(ii) by carbonic acid 1-chloro-2-methyl propyl ester 4-(methylsulfany) phenyl ester (3.50g, 12.74mmol), silver oxide (I) (2.95g, 12.74mmol) and isopropylformic acid. (13.00mL, 140.12mmol) mixture heat under an argon atmosphere to 95 DEG C, continue 2 hours. Reactant mixture it is cooled to rt and stirs overnight at rt, diluting with MTBE subsequently, filtered by kieselguhr and use more MTBE to wash. By the filtrate water (4x25mL) merged, sat.aq. sodium bicarbonate (2x25mL) washing, dry (Na2SO4), and evaporate isopropylformic acid. 2-methyl isophthalic acid-((4-(methylsulfany) phenoxy group) ketonic oxygen base) propyl ester obtaining 3.56g, use it for next step without being further purified.
(iii) by isopropylformic acid. 2-methyl isophthalic acid-((4-(methylsulfany) phenoxy group) ketonic oxygen base) propyl ester (3.56g, 10.91mmol) it is absorbed in acetone (30mL) and the mixture of water (7.50mL), last 5 minutes subsequently and add oxone (13.41g by part, 21.81mmol), stir 2 hours at rt subsequently. Filter reactant mixture and with MTBE (2x50mL) wash filtrate, this volume is reduced to 50mL (distilling out acetone) and mixture separating obtained between MTBE and water subsequently. By MTBE aqueous layer extracted and through Na2SO4The dry Organic substance merged, filters and evaporates the title compound obtaining 1.89g, using it for next step without being further purified.
Step B:
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester
By isopropylformic acid. 2-methyl isophthalic acid-((4-(methyl sulphonyl) phenoxy group) ketonic oxygen base) propyl ester (0.389g; 1.08mmol) solution in acetonitrile (2mL) is added into (S)-1-phenyl-2-(pyridine-2-base) ethamine (0.215g; 1.08mmol) with sodium bicarbonate (0.182g; 2.17mmol) in the agitated mixture in acetonitrile (3mL), and rt stirred reaction mixture 2 hours.Separate EtOAc and sataqNaHCO3, use sataqNaHCO3Washing organic layer also evaporates and obtains the material of 413mg, obtains isopropylformic acid. 2-methyl isophthalic acid-(S)-1-phenyl-2-(pyridine-2-base) the ethylaminocarbonyl oxygen base of 235mg through purification by column chromatography (the EtOAc gradient (0-50%) in use heptane)) mixture of two kinds of diastereomers of propyl ester.
The analysis of diastereomer and separate respectively with the flow velocity of 3mL/min at ChiralpakAD-H, 4.6*250mm; 5 μm use 10%MeOH/90%CO2, and with the flow velocity of 50mL/min at ChiralpakAD-H, 20*250mm; 5 μm use 10%MeOH/90%CO2Complete.
Embodiment 2, diastereomer 1
The diastereomer 1 of 105mg is obtained with 99% optical purity as the first eluting diastereomer by chiral separation. Rotamer mixture:
1HNMR (500MHz, DMSO-d6) δ ppm0.66-1.07 (m), 1.86 (m), 2.39 (m), 2.98-3.21 (m), 5.01 (m), 6.31 (m), 7.10-7.26 (m), 7.26-7.37 (m), 7.56-7.73 (m), 8.10 (d), 8.43-8.55 (m). Entirely without proton in spectrum: 28. Mainly/minor rotamer ratio: 1/0.15.
MS(ES+APCI+)m/z385(M+H)+
Embodiment 2, diastereomer 2
The diastereomer 2 of 104mg obtains as the second eluting diastereomer. Rotamer mixture:
1HNMR (500MHz, DMSO-d6) δ ppm0.48-0.69 (m), 0.75-0.87 (m), 0.87-1.07 (m), 1.73 (m), 1.85 (m), 2.40 (m), 2.98 (m), 3.03-3.18 (m), 4.97 (m), 6.22-6.38 (m), 7.13-7.26 (m), 7.26-7.37 (m), 7.65 (m), 7.78 (d), 8.06 (d), 8.48 (m). Entirely without proton in spectrum: 28. Mainly/minor rotamer ratio: 1/0.17.
MS(ES+APCI+)m/z385(M+H)+。
Optical purity=99%
Embodiment 3
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester
Owing to there being configuration two kinds possible at the carbon atom place represented with *, there is diastereomer two kinds different in embodiment 3. It is called embodiment 3 diastereomer 1 and embodiment 3 diastereomer 2. Do not determine its absolute configuration.
Step A:
Acetic acid 1-((4-(methyl sulphonyl) phenoxy group) ketonic oxygen base) ethyl ester
I () is by carbonic acid 1-chloroethene ester 4-(methylsulfany) phenyl ester (4.6g, 18.65mmol), silver oxide (I) (4.32g, 18.65mmol) and the mixture of acetic acid (11.75mL, 205.1mmol) heat under an argon atmosphere to 95 DEG C and continue 2 hours. Reactant mixture it is cooled to rt and dilutes with MTBE, being filtered by kieselguhr, and wash with more MTBE. By the filtrate water (4x25mL) merged, sat.aq. sodium bicarbonate (2x25mL) washing, dry (Na2SO4), and evaporate acetic acid 1-((4-(methylsulfany) phenoxy group) ketonic oxygen base) ethyl ester obtaining 1.79g, use it for next step without being further purified.
(ii) acetic acid 1-((4-(methylsulfany) phenoxy group) ketonic oxygen base) ethyl ester (1.79g, 6.62mmol) is absorbed in acetone (16mL) and the mixture of water (4.00mL). Last 5 minutes and add oxone (8.14g, 13.24mmol) by part, stir overnight at rt subsequently. Filter reactant mixture and wash with MTBE (2x50mL), volume is reduced to 50mL (distilling out acetone). Product is separated between MTBE and water. With MTBE aqueous layer extracted the dry Organic substance (Na merged2SO4), filter and evaporate the title compound obtaining 832mg, using it for next step without being further purified.
Step B:
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester
By acetic acid 1-((4-(methyl sulphonyl) phenoxy group) ketonic oxygen base) ethyl ester (302mg; 1.00mmol) solution in acetonitrile (1mL) is added into (S)-1-phenyl-2-(pyridine-2-base) ethamine (198mg; 1mmol) with sodium bicarbonate (168mg; 2.00mmol) in the stirring mixture in acetonitrile (4mL), and rt stirred reaction mixture 4 hours. Subsequently at EtOAc and sataqNaHCO3Between separating reaction mixture, use sataqNaHCO3, salt water washing organic layer, through Na2SO4Dry and evaporate. Obtaining the title compound of 160mg by column chromatography (using the EtOAc gradient (0-50%) in heptane) prepurification mixture, it is as the mixture of its two kinds of diastereomers.
The analysis of described diastereomer and separate respectively with the flow velocity of 3mL/min at PhenomenexLuxC4,4.6*250mm; 5 μm use 30%MeOH+DEA/70%CO2, and with the flow velocity of 50mL/min at PhenomenexLuxC4,20*250mm; 5 μm use 25%MeOH+DEA/75%CO2Complete.
Embodiment 3, diastereomer 1
The diastereomer 1 of 29mg is obtained with 99% optical purity as the first eluting diastereomer by chiral separation.
1HNMR (500MHz, DMSO-d6) δ ppm1.31 (d, 3H), 1.92 (s, 3H), 3.00-3.16 (m, 2H), 5.00 (td, 1H), 6.52 (q, 1H), 7.14-7.25 (m, 3H), 7.30 (d, 4H), 7.65 (t, 1H), 8.13 (d, 1H), 8.50 (d, 1H). Expand the signal in spectrum and do not see that DMSO-signal divides.
13CNMR(126MHz,DMSO-d6)δ19.6,20.7,44.6,54.9,88.7,121.6,123.8,126.4,126.9,128.3,136.2,143.0,149.0,153.2,158.0,168.6ppm。MS(ES+)m/z328(M+H)+。
Embodiment 3, diastereomer 2
The diastereomer 2 of 39mg obtains as the second eluting diastereomer.
1HNMR (500MHz, DMSO-d6) δ ppm1.32 (d, 3H), 1.95 (s, 3H), 3.01-3.18 (m, 2H), 5.00 (td, 1H), 6.53 (q, 1H), 7.13-7.24 (m, 3H), 7.29 (d, 4H), 7.65 (t, 1H), 8.17 (d, 1H), 8.49 (d, 1H). Expand the signal in spectrum and do not see that DMSO-signal divides.
13CNMR(126MHz,DMSO-d6)δ19.6,20.7,44.4,54.9,88.6,121.6,123.7,126.4,126.9,128.3,136.2,143.0,149.0,153.1,158.0,168.5.MS(ES+)m/z329(M+H)+。
Optical purity 98%.
Embodiment 4
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester
Owing to there being configuration two kinds possible at the carbon atom place represented with *, there is diastereomer two kinds different in embodiment 4. It is called embodiment 4 diastereomer 1 and embodiment 4 diastereomer 2. Do not determine its absolute configuration.
Step A:
Isopropylformic acid. 1-((4-(methyl sulphonyl) phenoxy group) ketonic oxygen base) ethyl ester
I 4-(methyl mercapto) phenol (4.91g, 35.00mmol) is absorbed in DCM (100mL) and is cooled to 0 DEG C by (). Add chloro-carbonic acid 1-chloroethene ester (1.888mL, 17.50mmol). The mixture 5 minutes being added dropwise over the 4-methyl morpholine (4.81mL, 43.74mmol) solution in DCM (20mL) for 10 minutes and obtaining in the stirring of this temperature is lasted at 0 DEG C. Rt stirred reaction mixture 180 minutes, dilute with DCM subsequently, wash (2x) with water, through Na2SO4Dry, filter and evaporation obtains carbonic acid 1-chloroethene ester 4-(methylsulfany) phenyl ester (6.94g), use it for next step without being further purified.
(ii) by carbonic acid 1-chloroethene ester 4-(methylsulfany) phenyl ester (2.3g, 9.32mmol), silver oxide (I) (2.160g, 9.32mmol) with isopropylformic acid. (9.51ml, 102.55mmol) mixture heat under an argon atmosphere to 95 DEG C, continue 2 hours. Reactant mixture it is cooled to rt and dilutes with MTBE, being filtered by kieselguhr, wash with more MTBE.The filtrate merged with water (4x25mL), sat.aq. sodium bicarbonate (2x25mL) washing, dry (Na2SO4) and evaporate the product obtaining 1.16g, use it for next step without being further purified.
(iii) isopropylformic acid. 1-((4-(methylsulfany) phenoxy group) ketonic oxygen base) ethyl ester (1.16g, 3.89mmol) is absorbed in acetone (12mL) and the mixture of water (3.00mL). Last 5 minutes and add oxone (4.78g, 7.78mmol) by part, stir overnight at rt subsequently. Filter reactant mixture and with MTBE (2x50mL) wash filtrate, by distilling out acetone, volume is reduced to about 50mL, separate between MTBE and water subsequently. By MTBE aqueous layer extracted and through Na2SO4The dry Organic substance merged, filters and evaporates the title compound obtaining 531mg, using it for next step without being further purified.
Step B
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester
By isopropylformic acid. 1-((4-(methyl sulphonyl) phenoxy group) ketonic oxygen base) ethyl ester (0.500g; 1.51mmol) solution in acetonitrile (2mL) is added into (S)-1-phenyl-2-(pyridine-2-base) ethamine (0.300g; 1.51mmol) with sodium bicarbonate (0.254g; 3.03mmol) in the agitated mixture in acetonitrile (6mL), and reactant mixture is stirred overnight. At EtOAc and sataqNaHCO3Between separating mixture, use sataqNaHCO3, salt water washing organic layer, through Na2SO4Dry and evaporate and obtain 0.70g., obtained the title compound (0.309g, 57.2%) of the mixture as two kinds of diastereomers by purification by column chromatography (using the EtOAc gradient (0-50%) in heptane).
The analysis of diastereomer and separate respectively with the flow velocity of 3mL/min at PhenomenexLuxC4,4.6*250mm; 5 μm use 15%MeOH+DEA/85%CO2, and with the flow velocity of 50mL/min at PhenomenexLuxC4,20*250mm; 5 μm use 15%MeOH+DEA/85%CO2Complete.
Embodiment 4, diastereomer 1
The diastereomer 1 of 25mg is obtained with 99% optical purity as the first eluting diastereomer by chiral separation. Rotamer mixture:
1HNMR (500MHz, DMSO-d6) δ ppm0.86-1.05 (m), 1.19 (d), 1.32 (d), 2.31-2.44 (m), 2.98-3.20 (m), 4.94-5.07 (m), 6.48 (d), 6.52 (q), 7.15-7.25 (m), 7.25-7.34 (m), 7.60-7.70 (m), 7.77 (d), 8.06-8.18 (m), 8.44-8.55 (m). Entirely without proton in spectrum: 24. Mainly/secondary ratio: 1:0.07.
MS(ES+APCI+)m/z357(M+H)+。
UV purity=100%.
Embodiment 4, diastereomer 2
The diastereomer 2 of 25mg obtains as the second eluting isomer. Rotamer mixture:
1HNMR (500MHz, DMSO-d6) dppm0.82-0.94 (m), 0.94-1.04 (m), 1.25 (d), 1.32 (d), 2.24-2.32 (m), 2.34-2.44 (m), 3.00-3.17 (m), 5.02 (td), 6.48 (d), 6.52 (q), 7.15-7.25 (m), 7.25-7.38 (m), 7.55-7.77 (m), 8.16 (d), 8.44-8.57 (m). entirely without proton in spectrum: 24. Mainly/secondary ratio: 1:0.08.
MS(ES+APCI+)m/z357(M+H)+.
UV purity=100%.
Optical purity=99%.
Embodiment 5-12 uses general intermediate, now its preparation is illustrated.
Preparation for the versatile intermediates of embodiment 5-12
2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridinium dichloride (it is alternatively referred to as: (S)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-carboxamide dihydrochloride)
Step A
(S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester
At 0 DEG C by T3P (50%wt. in DMF, 0.86mL, 1.47mmol) it is added dropwise over to (1S)-1-phenyl-2-(pyridine-2-base) second-1-amine (200mg, 0.737mmol), Boc-L-proline (159mg, 0.737mmol) with DIPEA (0.64mL, 3.69mmol) at CH2Cl2(7.4mL) solution in.Reactant mixture is warmed to rt gradually stir overnight simultaneously. Use 5%aq.NaHCO3Washing organic layer twice, with salt water washing once, through Na2SO4Dry, filter and concentrate. Use 50gSnap column purification product (with MeOH and CH2Cl2Gradient elution (0%MeOH/100%CH2Cl2→ 10%MeOH/90%CH2Cl2)), obtain title compound 305mg (> 100%).
1HNMR(300MHz,CDCl3):ppm1.35(s,9H),1.70–1.90(m,2H),2.05–2.19(m,2H),3.13(dd,1H),3.29–3.39(m,1H),3.46–3.62(m,2H),4.20–4.29(m,2H),5.39(q,1H),6.91(d,1H),7.09–7.14(m,1H),7.16–7.23(m,5H),7.49(td,1H),8.45–8.59(m,1H).
Interchangeable method:
Boc-L-Pro-OH (2.0g, 9.29mmol) is dissolved in dry DMF (15mL). Add HATU (3.7g, 9.76mmol) and permitted the uncommon alkali (5.3mL, 30.66mmol) of Buddhist nun and stir mixture 30 minutes at rt. Subsequently, 2-[(2S)-2-amino-2-phenylethyl] pyridine-1-dichloride (2.5g, 9.29mmol) is added into solution and stirs mixture 3 hours 30 minutes at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2Purified product on post (with gradient (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 10%MeOH/90%EtOAc/0% heptane) eluting) and subsequently purification (gradient (0-100%MeOH) eluting with MeOH and water) on C-18 post, obtain the title compound of 2.9g (78%).
1HNMR(300MHz,CDCl3): ppm1.35 (s, 9H), 1.70 1.90 (m, 2H), 2.05 2.19 (m, 2H), 3.13 (dd, J=13.8,7.1Hz, 1H), 3.29 3.39 (m, 1H), 3.46 3.62 (m, 2H), 4.20 4.29 (m, 1H), 5.39 (q, J=6.8Hz, 1H), 6.91 (d, J=7.3Hz, 1H), 7.09 7.14 (m, 1H), 7.16 7.23 (m, 5H), 7.49 (td, J=7.63,1.8Hz, 1H), 8.45 8.59 (m, 1H).
Step B
(S)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-carboxamide dihydrochloride
At 0 DEG C; by (S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (305mg; 0.771mmol) it is dissolved in 4MHCl 1; solution (7.7mL, 30.8mmol) in 4-dioxane. Reactant mixture is warmed to rt gradually stir overnight simultaneously. Under vacuo remove volatile matter and in MTBE grinding product. Solid is recovered by filtration on a buchner funnel, washs with MTBE and dry under vacuo, it is thus achieved that for 263mg (93%) title compound of dihydrochloride.
1HNMR(300MHz,DMSO-d6):ppm1.61–1.84(m,3H),2.30–2.36(m,1H),3.05–3.11(m,2H),3.39–3.47(m,2H),4.05–4.20(m,2H),5.34(q,1H),7.17–7.41(m,5H),8.20–8.42(m,1H),8.67–8.75(m,1H),9.45–9.62(m,2H).
Interchangeable method:
By (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-2-base) ethyl] carbamoyl } pyrrolidine-1-carboxylic acid tert-butyl ester (2.9g; 7.33mmol) it is dissolved in 4MHCl 1; in solution (73mL, 293.31mmol) in 4-dioxane. Rt stirred reaction mixture 3 hours. Under vacuo remove volatile matter and in MTBE grinding product. Solid is recovered by filtration on a buchner funnel; wash with MTBE and dry under vacuo, it is thus achieved that (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-1--2-base) ethyl] carbamoyl of 2.7g (100%) pyrrolidine-1-.
1HNMR(300MHz,D2: ppm1.66 1.83 (m, 3H), O) 2.20 2.26 (m, 1H), 3.14 (t, J=6.9Hz, 2H), 3.34 (dd, J=14.1,8.2Hz, 1H), 3.51 (dd, J=14.4,7.3Hz, 1H), 4.18 (dd, J=8.5,6.2Hz, 1H), 5.11 (t, J=7.9Hz, 1H), 7.06 7.10 (m, 2H), 7.15 7.21 (m, 3H), 7.61 7.70 (m, 2H), 8.23 (dt, J=7.9,1.5Hz, 1H), 8.37 (d, J=5.8Hz, 1H).
Embodiment 5
(S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide
Preparing title compound, it is the dihydrochloride of (S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide.
Step A
(S)-3-methyl isophthalic acid-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) fourth-2-carbamate
At 0 DEG C by T3P (50%wt. in DMF, 0.83mL, 1.42mmol) it is added dropwise over to (S)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-carboxamide dihydrochloride (263mg, 0.714mmol), Boc-L-valine (155mg, 0.714mmol) and the DIPEA (0.62mL, 3.57mmol) solution in DCM (7mL) in. Under agitation warm reactant mixture to rt overnight gradually. Use 5%aq.NaHCO3Washing organic layer twice, with salt water washing once, through Na2SO4Dry, filter and concentrate. Use 50gSnap column purification product (with MeOH and CH2Cl2Gradient (5%MeOH/95%CH2Cl2→ 10%MeOH/90%CH2Cl2) eluting), obtain title compound 258mg (73%).
1HNMR(300MHz,CDCl3):ppm0.91(d,3H),1.00(d,3H),1.43(s,9H),1.85–1.99(m,2H),2.00–2.16(m,1H),2.17–2.21(m,1H),3.12–3.27(m,2H),3.47–3.62(m,1H),3.63–3.78(m,1H),4.32(dd,1H),4.58(d,1H),5.23–5.35(m,2H),6.97(d,1H),7.10(dd,1H),7.14–7.30(m,5H),7.50(td,1H),7.84(d,1H),8.48(dd,1H).
Step B
(S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-carboxamide dihydrochloride
By (S)-3-methyl isophthalic acid-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) fourth-2-carbamate (258mg; 0.522mmol) it is dissolved in 4MHCl 1; in solution (5.2mL, 30.8mmol) in 4-dioxane. Stirred reaction mixture is overnight. Under vacuo remove volatile matter and in EtOAc grinding product. Solid is recovered by filtration on a buchner funnel, subsequently at Et2O grinds. After filtering on a buchner funnel, drying solid under vacuo, it is thus achieved that the title compound of 200mg (82%), it is dihydrochloride. To be free alkali by technical transform known to those skilled in the art as the title compound of dihydrochloride subsequently. Alternatively, title compound can be prepared by method known to those skilled in the art as fumarate.
1HNMR(300MHz,CD3OD):ppm0.97(d,3H),1.04(d,3H),1.68-1.79(m,1H),1.86-2.05(m,2H),2.13-2.27(m,2H),3.50-3.61(m,3H),3.68-3.75(m,1H),4.02(d,1H),4.45(dd,1H),5.40(dd,1H),7.31-7.43(m,5H),7.90(t,1H),8.02(d,1H),8.51(td,1H),8.75(d,1H).
[M+H] +=395.27
Embodiment 6
(S)-1-((S)-2,6-diaminourea caproyl)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide
Preparing title compound, it is 2-[(2S)-2-{ [(2S)-1-[(2S)-2,5-diaminourea caproyl] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-terchoride
Step A
(S) own-1,5-two base diamino acid tert-butyl ester of-6-oxo-6-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl)
N-α, N-ε-two (tert-butoxycarbonyl)-1B dicyclohexyl ammonium salt (287mg, 0.54mmol) is dissolved in dry DMF (4mL). Add HATU (217mg, 0.57mmol) and DIPEA (0.21mL, 1.19mmol) and stir mixture 30 minutes at rt. Subsequently; by (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-1--2-base) ethyl] carbamoyl } pyrrolidine-1-dichloride (200mg, 0.54mmol) is added into solution and stirs mixture 18 hours at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2Purified product (with gradient (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 10%MeOH/90%EtOAc/0% heptane) eluting) on post, purification (gradient (0-100%MeOH) eluting with MeOH and water) on C-18 post, obtains the title compound of 80mg (24%) subsequently.
1HNMR(300MHz,CDCl3):ppm1.34–1.39(m,2H),1.41(s,9H),1.43(s,9H),1.52–1.64(m,3H),1.68–2.02(m,4H),2.08–2.22(m,2H),3.02–3.16(m,3H),3.20–3.28(m,1H),3.48–3.57(m,1H),3.60–3.70(m,1H),4.40–4.51(m,1H),4.54–4.57(m,1H),4.97–5.08(m,1H),5,29-5.39(m,2H),7.00(d,1H),7.10–7.32(m,6H),7.52(td,1H),7.86(d,1H),8.49(d,1H).
Step B
The synthesis of 2-[(2S)-2-{ [(2S)-1-[(2S)-2,5-diaminourea caproyl] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-terchoride
By (S)-6-oxo-6-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) own-1; the 5-bis-base diamino acid tert-butyl ester (80mg; 0.13mmol) it is dissolved in 4MHCl 1; solution (1.6mL, 6.4mmol) in 4-dioxane.Rt stirred reaction mixture 18 hours. Under vacuo remove volatile matter and in MTBE grinding product. Solid is recovered by filtration on a buchner funnel, washs with MTBE and dry under vacuo. Solid is dissolved in water and lyophilization obtains the title compound of 60mg (88%).
1HNMR(300MHz,D2O): ppm1.23-1.35 (m, 2H), 1.46-1.59 (m, 3H), 1.65-1.80 (m, 4H), 2.04-2.13 (m, 1H), 2.80 (t, 2H), 3.31-3.43 (m, 2H), 3.47-3.57 (m, 2H), 4.16 (t, 1H), 4.28 (t, 1H), 5.11 (t, 1H), 7.10-7.13 (m, 2H), 7.16-7.26 (m, 3H), 7.68-7.73 (m, 2H), 8.31 (td, 1H), 8.42 (dd, 1H);
[M+H]+=424.2.
Embodiment 7
(S)-1-((S)-2-amino-3-(1H-imidazol-4 yl) propiono)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide
Preparing title compound, it is 2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-3-(1H-imidazoles-1--4-base) propiono] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-terchoride
Step A
(S)-3-(1H-imidazol-4 yl)-1-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate
Boc-His-OH (166mg, 0.65mmol) is dissolved in dry DMF (4mL). Add HATU (260mg, 0.68mmol) and DIPEA (0.38mL, 2.85mmol) and stir mixture 30 molecule at rt. Subsequently, add 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridinium chloride (240mg, 0.65mmol) and stir mixture 66 hours at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2On post, purified product is (with MeOH and CH2Cl2Gradient (0%-13%MeOH) eluting), purification (gradient (0-100%MeOH) eluting by the gradient of MeOH and water) on C-18 post, obtains the title compound of 100mg (29%) subsequently.
1HNMR(300MHz,CDCl3):ppm1.44(s,9H),1.77–2.00(m,3H),2.05–2.19(m,1H),3.03–3.14(m,2H),3.23(dd,1H),3.40(dd,1H),3.52–3.58(m,1H),4.50–4.62(m,2H),5,43-5.50(m,2H),6.91–6.97(m,2H),7.13–7.27(m,5H),7.53(t,1H),7.65(s,1H),8.53(d,1H),8.67(d,1H).
Step B
2-((S)-2-((S)-1-((S)-2-amino-3-(1H-imidazoles-1--4-base) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine terchoride
By (S)-3-(1H-imidazol-4 yl)-1-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate (100mg; 0.19mmol) it is dissolved in 4MHCl 1; in solution (2.3mL, 9.39mmol) in 4-dioxane. Rt stirred reaction mixture 18 hours. Under vacuo remove volatile matter and in MTBE grinding product. Solid is recovered by filtration on a buchner funnel, washs with MTBE and dry under vacuo. Soluble in water for described solid and lyophilization are obtained the title compound of 85mg (69%).
1HNMR(300MHz,D2: ppm1.50-1.58 (m, 1H), O) 1.69-1.76 (m, 2H), 2.07-2.14 (m, 1H), 3.12-3.21 (m, 3H), 3.38 (dd, 7.3Hz, 1H), 3.48-3.56 (m, 2H), 4.32 (t, 1H), 4.43 (t, 1H), 5.14 (t, 1H), 7.08-7.12 (m, 2H), 7.15-7.23 (m, 3H), 7.26 (s, 1H), 7.65-7.70 (m, 2H), 8.26 (td, 1H), 8.39 (d, 1H), 8.49 (d, 1H);
[M+H]+=433.2;
[M+Na]+=455.1.
Embodiment 8
2-((S)-2-((S)-1-((S)-2-amino-3-(4-hydroxy phenyl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine dihydrochloride
Title compound is also referred to as: and 2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-3-(4-hydroxy phenyl) propiono] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-dichloride
Step A
(S)-3-(4-hydroxy phenyl)-1-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate
Boc-Tyr-OH (229mg, 0.81mmol) is dissolved in dry DMF (5mL).Add HATU (325mg, 0.86mmol) and DIPEA (0.47mL, 2.69mmol) and stir mixture 30 minutes at rt. Subsequently, 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridinium chloride (300mg, 0.81mmol) is added into solution and stirs mixture 66 hours at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2Purified product (with (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 15%MeOH/85%EtOAc/0% heptane) eluting) on post, purification (gradient (0-100%MeOH) eluting with MeOH and water) on C-18 post, obtains the title compound of 180mg (40%) subsequently.
1HNMR(300MHz,CDCl3):ppm1.44(s,9H),1.73–2.02(m,3H),2.16–2.22(m,1H),2.92–3.09(m,4H),3.35–3.42(m,1H),3.48–3.51(m,1H),3.53–3.68(m,1H),4.48–4.51(m,1H),4.65–4.73(m,1H),5.06–5.14(m,1H),5.43(d,1H),6.61(d,1H),6.86(d,,2H),6.94–6.99(m,2H),7.08–7.26(m,6H),7.42(dd,1H),8.49(d,1H),8.63(s,1H).
Step B:
2-((S)-2-((S)-1-((S)-2-amino-3-(4-hydroxy phenyl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridinium dichloride
By (S)-3-(4-hydroxy phenyl)-1-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate (180mg; 0.32mmol) it is dissolved in 4MHCl 1; in solution (3.2mL, 12.89mmol) in 4-dioxane. Rt stirred reaction mixture 18 hours. Under vacuo remove volatile matter and in MTBE grinding product. Solid is recovered by filtration on a buchner funnel, washs with MTBE and dry under vacuo. Described solid is dissolved in water and lyophilization obtains the title compound of 150mg (88%).
1HNMR(300MHz,D2O): ppm1.48-1.57 (m, 1H), 1.68-1.73 (m, 2H), 1.98-2.05 (m, 1H), 2.68-2.76 (m, 1H), 2.93-3.00 (m, 1H), 3.10-3.19 (m, 1H), 3.40-3.63 (m, 3H), 4.20-4.28 (m, 2H), 5.14 (t, 1H), 6.65 (d, 2H), 6.96 (d, 2H), 7.13-7.22 (m, 5H), 7.63-7.66 (m, 2H), 8.19-8.22 (m, 1H), 8.40 (d, 1H);
[M+H]+=459.2.
Embodiment 9
2-((S)-2-((S)-1-((S)-2-amino-3-(1H-indol-3-yl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine dihydrochloride
Title compound is also referred to as: and 2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-3-(1H-indol-3-yl) propiono] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-dichloride
Step A
(S)-3-(1H-indol-3-yl)-1-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate
Boc-Trp-OH (207mg, 0.68mmol) is dissolved in dry DMF (4mL). Add HATU (271mg, 0.71mmol) and DIPEA (0.39mL, 2.24mmol) and mixture be stirred at room temperature 30 minutes. Subsequently; add (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-1--2-base) ethyl] carbamoyl } pyrrolidine-1-dichloride (250mg, 0.68mmol) stir mixture 18 hours at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2On post, purified product (with gradient (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 15%MeOH/85%EtOAc/0% heptane) eluting), obtains the title compound of 410mg (quantization).
1HNMR(300MHz,CDCl3):ppm1.44(s,9H),1.77–1.89(m,3H),2.14–2.24(m,1H),3.03–3.24(m,4H),3.28–3.36(m,2H),3.54–3.65(m,1H),4.52–4.58(m,1H),4.79–4.88(m,1H),5,12-5.27(m,1H),5.34–5.41(m,1H),6.63(d,1H),6.94–7.31(m,8H),7.38–7.53(m,3H),7.62–7.67(m,1H),8.59(d,1H),9.87(s,1H).
Step B
2-((S)-2-((S)-1-((S)-2-amino-3-(1H-indol-3-yl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridinium dichloride
(S)-3-(1H-indol-3-yl)-1-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate (395mg, 0.68mmol) is dissolved in 1MHCl at Et2In solution (27.0mL, 27.20mmol) in O.Rt stirred reaction mixture 4 hours. At Et2Grinding product solid is recovered by filtration on a buchner funnel in O, uses Et2O washing also dries under vacuo. Described solid is dissolved in water and cool drying obtains the title compound of 175mg (44%).
1HNMR(300MHz,D2: ppm1.41-1.53 (m, 1H), O) 1.63-1.72 (m, 2H), 1.93-2.04 (m, 1H), 2.85 (dd, 1H), 2.94-3.55 (m, 5H), 4.19-4.31 (m, 2H), 5.08 (t, 1H), 6.90-7.31 (m, 9H), 7.38 (d, 1H), 7.55-7.58 (m, 2H), 8.15 (t, 1H), 8.31 (d, 1H);
[M+H]+=482.2,
[M+Na]+=504.1.
Embodiment 10
(S)-1-((S)-2-amino-3-PHENYLPROPIONYL)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide
Preparing title compound, it is 2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-3-PHENYLPROPIONYL] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-dichloride
Step A
(S)-1-oxo-3-phenyl-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate
Boc-Phe-OH (180mg, 0.68mmol) is dissolved in dry DMF (4mL). Add HATU (271mg, 0.71mmol) and DIPEA (0.39mL, 2.24mmol) and stir mixture 30 minutes at rt. Subsequently; by (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-1--2-base) ethyl] carbamoyl } pyrrolidine-1-dichloride (250mg, 0.68mmol) is added into solution and stirs mixture 18 hours at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2Purified product (with gradient (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 15%MeOH/85%EtOAc/0% heptane) eluting) on post, purification (gradient (0-100%MeOH) eluting with MeOH and water) on C-18 post, obtains the title compound of 170mg (46%) subsequently.
1HNMR(300MHz,CDCl3):ppm1.44(s,9H),1.73–1.91(m,3H),2.10–2.19(m,1H),3.10–3.40(m,3H),3.45–3.61(m,2H),4.27–4.35(m,1H),4.50–4.56(m,1H),4.60–4.69(m,1H),5,17-5.41(m,3H),6.93–7.03(m,2H),7.06–7.32(m,9H),7.47–7.56(m,1H),7.82(d,1H),8.48(d,1H).
Step B
2-((S)-2-((S)-1-((S)-2-amino-3-PHENYLPROPIONYL) pyrrolidine-2-formamido group)-2-phenylethyl) pyridinium dichloride
(S)-1-oxo-3-phenyl-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) the third-2-carbamate (170mg, 0.31mmol) is dissolved in 1MHCl at Et2In solution (12.5mL, 12.53mmol) in O. Rt stirred reaction mixture 18 hours. At Et2Grinding product in O. Solid is recovered by filtration on a buchner funnel, uses Et2O washing also dries under vacuo. Described solid is dissolved in water and lyophilization obtains the title compound of 150mg (93%).
1HNMR(300MHz,D2: ppm1.39-1.48 (m, 1H), O) 1.58-1.65 (m, 2H), 1.92-1.99 (m, 1H), 2.66-2.74 (m, 1H), 2.95-3.10 (m, 2H), 3.29-3.45 (m, 3H), 4.15-4.27 (m, 2H), 5.09 (t, 1H), 6.97-7.17 (m, 10H), 7.59-7.64 (m, 2H), 8.18 (t, 1H), 8.35 (d, 1H);
[M+H]+=443.3,
[M+Na]+=465.2.
Embodiment 11
(S)-1-((S)-2-amino-4-methylvaleryl)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide
Preparing title compound, it is 2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-4-methylvaleryl] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-dichloride.
Step A
(S)-4-methyl isophthalic acid-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) penta-2-carbamate
N-(tert-butoxycarbonyl)-L-Leu (157mg, 0.68mmol) is dissolved in dry DMF (4mL).Add HATU (271mg, 0.71mmol) and DIPEA (0.39mL, 2.24mmol) and stir mixture 30 minutes at rt. Subsequently; adding (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-1--2-base) ethyl] carbamoyl } pyrrolidine-1-dichloride (250mg, 0.68mmol) stirs mixture 18 hours to solution and at rt. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2Purified product (with gradient (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 15%MeOH/85%EtOAc/0% heptane) eluting) on post, purification (gradient (0-100%MeOH) eluting with MeOH and water) on C-18 post, obtains the title compound of 200mg (58%) subsequently.
1HNMR(300MHz,CDCl3): ppm0.91 (d, 3H), 0.98 (d, 3H), 1.34 1.52 (m, 1H), 1.41 (s, 9H), 1.70 1.84 (m, 2H), 1.85 1.96 (m, 3H), 2.11 2.18 (m, 1H), 3.07 3.27 (m, 2H), 3.47 3.56 (m, 1H), 3.61 3.71 (m, 1H), 4.43 4.56 (m, 2H), 5.14 5.18 (m, 1H), 5,26-5.34 (m, 1H), 6.98 (d, J=7.7Hz, 1H), 7.08 7.25 (m, 5H), 7.52 (t, 1H), 7.83 (d, 1H), 8.48 (d, 1H).
Step B
2-((S)-2-((S)-1-((S)-2-amino-4-methylvaleryl) pyrrolidine-2-formamido group)-2-phenylethyl) pyridinium dichloride
(S)-4-methyl isophthalic acid-oxo-1-((S)-2-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl) pyrrolidin-1-yl) penta-2-carbamate (200mg, 0.39mmol) is dissolved in 1MHCl at Et2In solution (15.7mL, 15.7mmol) in O. Rt stirred reaction mixture 18 hours. At Et2Grinding product in O. Solid is recovered by filtration on a buchner funnel, uses Et2O washing also dries under vacuo. Solid is dissolved in water and lyophilization obtains the title compound of 130mg (69%).
1HNMR(300MHz,D2: ppm0.72 (d, 6H), O) 1.31-1.49 (m, 4H), 1.65-1.74 (m, 2H), 1.93-2.02 (m, 1H), 3.23-3.49 (m, 4H), 3.99-4.04 (m, 1H), 4.16-4.21 (m, 1H), 5.07 (t, 1H), 7.08-7.20 (m, 5H), 7.63-7.67 (m, 2H), 8.22 (td, 1H), 8.37 (dd, 1H);
[M+H]+=409.2,
[M+Na]+=431.2.
Embodiment 12
2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-5-{ [amino (imino group) methyl] amino } valeryl]-pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-tetrachloride
Step A
N-[(1Z)-[(4S)-4-{ [(tert-butoxy) carbonyl] amino }-5-oxo-5-[(2S)-2-{ [(1S)-1-phenyl-2-(pyridine-2-base) ethyl] carbamoyl } pyrrolidin-1-yl] amyl group] amino } ({ [(tert-butoxy) carbonyl] imino group }) methyl] t-butyl carbamate
By Boc-Arg (Boc)2-OH (644mg, 1.36mmol) is dissolved in dry DMF (7mL). Add HATU (542mg, 1.43mmol) and DIPEA (0.78mL, 4.48mmol) and stir mixture 30 minutes at rt. Subsequently; add (2S)-2-{ [(1S)-1-phenyl-2-(pyridine-1--2-base) ethyl] carbamoyl pyrrolidine-1-dichloride (500mg, 1.36mmol) to solution and rt stir 18 hours. Add water and extract mixture with EtOAc3x. By salt water washing organic facies, through Na2SO4Dry, filter and concentrating under reduced pressure. At SiO2Purification (with gradient (0%MeOH/50%EtOAc/50% heptane → 0%MeOH/100%EtOAc/0% heptane → 10%MeOH/90%EtOAc/0% heptane) eluting) on post, purification (gradient (0-100%MeOH) eluting with MeOH and water) on C-18 post subsequently, it is thus achieved that the title compound of 200mg (20%).
1HNMR(300MHz,CDCl3):ppm1.43(s,9H),1.46(s,9H),1.51(s,9H),1.57–1.76(m,4H),1.86–1.99(m,3H),2.12–2.25(m,1H),3.11(dd,1H),3.23–3.30(m,1H),3.58–3.95(m,4H),4.42(t,,1H),4.56(d,1H),5,31-5.38(m,2H),6.98(d,1H),7.17–7.33(m,5H),7.54(t,1H),7.93(d,1H),8.56(d,1H).
Step B
2-[(2S)-2-{ [(2S)-1-[(2S)-2-amino-5-{ [amino (imino group) methyl] amino } valeryl] pyrrolidin-2-yl] formamido group }-2-phenylethyl] pyridine-1-tetrachloride
By N-[-5-oxo-5-[(2S)-2-{ [(1S)-1-phenyl-2-(pyridine-2-base) ethyl] carbamoyl } pyrrolidin-1-yl] amyl group (1Z)-{ [(4S)-4-{ [(tert-butoxy) carbonyl] amino }] amino } ({ [(tert-butoxy) carbonyl] imino group }) methyl] t-butyl carbamate (200mg, 0.27mmol) is dissolved in 1MHCl at Et2In solution (5.3mL, 10.64mmol) in O. Rt stirred reaction mixture 18 hours. At Et2Grinding product in O. Solid is recovered by filtration on a buchner funnel, uses Et2O washing also dries under vacuo. Described solid is dissolved in water and lyophilization obtains the title compound of 140mg (88%).
1HNMR(300MHz,D2O): ppm1.31-1.57 (m, 3H), 1.66-1.78 (m, 4H), 2.00-2.10 (m, 1H), 2.99 (t, 2H), 3.28-3.40 (m, 4H), 4.16 (t, 1H), 4.26 (t, 1H), 5.09 (t, 1H), 7.10-7.13 (m, 2H), 7.16-7.21 (m, 3H), 7.67-7.71 (m, 2H), 8.27 (t, 1H), 8.40 (d, 1H);
[M+H]+=452.2.
Biological activity
Prodrug as herein described expection is orally administered to the experimenter suffering from depression or pain.
Embodiment 13
This example illustrates the prodrug of different (S)-1-phenyl-2-(pyridine-2-base) ethamine, wherein R1 is C1-6Alkyl C (O) O (C1-6Alkoxyl), its different rates (namely slow or fast) that can be used for realizing converting to (S)-1-phenyl-2-(pyridine-2-base) ethamine is distributed to verify suitable PK. Therefore, change R1 and cause the different pharmacokinetic profiles of (S)-1-phenyl-2-(pyridine-2-base) ethamine to produce different prodrugs. Additionally, this embodiment shows when pro-drug conversion is become free alkali, oral exposure is absent from expected loss. Wherein R1 is C1-6Alkyl C (O) O (C1-6Alkoxyl) conversion from prodrug to (S)-1-phenyl-2-(pyridine-2-base) ethamine expect via following generation: the enzyme hydrolysis of initial functional group such as ester, with the spontaneous nuclear transformation of backward (S)-1-phenyl-2-(pyridine-2-base) ethamine. The enzyme expection participated in is several esterases non-specific, high power capacity, and it can pass through following display: uses non-selective esterase inhibitor to suppress to convert, and uses selective depressant not suppress to convert. The expection of this esterase is distributed in the whole body of people. People's intestinal juice (HIF), people's liver S9 component and people's whole blood have been used for checking the pharmacokinetic properties of (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug and in different body compartments the synthesis speed of (S)-1-phenyl-2-(pyridine-2-base) ethamine and form degree. By the different prodrugs of (S)-1-phenyl-2-(pyridine-2-base) ethamine formed the speed of (S)-1-phenyl-2-(pyridine-2-base) ethamine in whole measurements determination dramatically different, as shown in table 1.
Table 1
In table 1, the in vitro results of display shows that the different pharmacokinetics blood plasma distribution of (S)-1-phenyl-2-(pyridine-2-base) ethamine can by using different (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrugs to realize. Therefore, the pharmacokinetic profiles that the selection of specific prodrug will allow for different (S)-1-phenyl-2-(pyridine-2-base) ethamine, it is to say, can be used for different prodrugs realizing the slow or fast conversion to (S)-1-phenyl-2-(pyridine-2-base) ethamine. People's intestinal juice (HIF), people's liver and the human blood used measures to generate the result of table 1 display, it is at MalmborgJ&PloegerBA, .JPharmacolToxicolMethods (2013) May-Jun67 (3) 203-13 is described, and it is incorporated herein by the mode introduced.
Embodiment 14
This embodiment shows to use the wherein R1 beThe prodrug of different (S)-1-phenyl-2-(pyridine-2-base) ethamine verify suitable PK with the different rates (namely slow or fast) realizing changing into (S)-1-phenyl-2-(pyridine-2-base) ethamine and be distributed. Therefore, change R1 and cause the different pharmacokinetic profiles of (S)-1-phenyl-2-(pyridine-2-base) ethamine to produce different prodrugs. Additionally, this embodiment shows to be absent from expected loss when being free alkali by pro-drug conversion in oral exposure.
Wherein R1 isThe prodrug of formula (I) compound occur to the expection that converts of (S)-1-phenyl-2-(pyridine-2-base) ethamine via the enzyme hydrolysis in proline C-end, thus discharging dipeptides and (S)-1-phenyl-2-(pyridine-2-base) ethamine. The enzyme participated in is contemplated to DPP IV (DPPIV), and it can pass through to suppress to be converted display with the selective depressant of this enzyme. DPPIV expection is distributed in the whole body of people. People's intestinal juice (HIF), people's liver S9 component and people's whole blood have been used for checking the synthesis speed of (S)-1-phenyl-2-(pyridine-2-base) ethamine in the pharmacokinetic properties of (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug and different body compartment and forming degree. Caco-2 cell has been used for the permeability of the prodrug of assessment (S)-1-phenyl-2-(pyridine-2-base) ethamine and absorbs potentiality. By different (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrugs formed the speed of (S)-1-phenyl-2-(pyridine-2-base) ethamine in measurements determination different, particularly in human blood, as shown in table 2. The different permeability shown by the different prodrugs of (S)-1-phenyl-2-(pyridine-2-base) ethamine shows that the systemic exposure of the prodrug of (S)-1-phenyl-2-(pyridine-2-base) ethamine will depend upon which selected prodrug and different.
Table 2
External test shows that the different pharmacokinetics blood plasma distribution of (S)-1-phenyl-2-(pyridine-2-base) ethamine can be passed through to use different prodrugs to realize. Therefore, the different pharmacokinetic profiles of (S)-1-phenyl-2-(pyridine-2-base) ethamine can be passed through to use different prodrugs to realize.
Embodiment 15
This embodiment illustrates that the oral administration of prodrug of (S)-1-phenyl-2-(pyridine-2-base) ethamine has similar pharmacokinetic profiles to the IV1 h infusion of (S)-1-phenyl-2-(pyridine-2-base) ethamine.
Based on vitro data, (S)-1-phenyl-2-(pyridine-2-base) ethamine (lanicemine, lanicemine) it is shown in people and there is good oral administration biaavailability (> 75%), but there is the Cmax (relatively the safety distribution of its 1 h infusion) higher than acceptable level when giving as intravenous push. The one of practicality and availability for assessing (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug selects standard to be when directly prodrug is entered blood flow, and this prodrug is retaining oral/1 hour iv infusion feature (such as T of (S)-1-phenyl-2-(pyridine-2-base) ethaminemax、Cmax, AUC) while reduce active part CmaxPotentiality, thus reduce the safety risks that possible abuse (such as abuse liability) and/or Cmax drive. As differentiating the mode of prodrug with suitable pharmacokinetic profiles in people, construct many compartments for (S)-1-phenyl-2-(pyridine-2-base) ethamine and every kind of prodrug considered, based on physiological pharmacokinetic model (PBPK). Use can demonstrate PBPK model (referring to MalmborgJ&PloegerBA for its a series of known prodrug obtaining people's PK data, .JPharmacolToxicolMethods (2013) May-Jun67 (3) 203-13, it is incorporated herein by the mode introduced).The speed constant used in a model is based on the stabilization in vitro Journal of Sex Research (i.e. people's intestinal juice, human blood etc.) carried out with prodrug and (S)-1-phenyl-2-(pyridine-2-base) ethamine (embodiment value is shown in table 1 and 2).
Table 3 shows the key pharmacokinetics prediction of the prodrug for an embodiment 5-DPPIV fracture. Enumerate in table 3, when given peroral dosage form pulverize not appropriately as inject i.v. give to deliver time, it was predicted that the Cmax of (S)-1-phenyl-2-(pyridine-2-base) ethamine exposes to be increased > 2x. In contrast, from (S)-1-phenyl-2-(pyridine-2-base) ethamine of the prodrug release being orally administered to, there is the PK distribution similar to 1 h infusion of (S)-1-phenyl-2-(pyridine-2-base) ethamine, and when as when injecting i.v. administration, double without Cmax. In addition, owing to driving to the conversion of (S)-1-phenyl-2-(pyridine-2-base) ethamine by DPPIV selectivity, DPPIV inhibitor can be used in intentional or involuntary abuse to stop converting, and this makes the security features increased embed in this DPPIV prodrug design.
In table 3, compound 1 is (S)-1-phenyl-2-(pyridine-2-base) ethamine. In table 3, all dosage is chosen as the compound 1 [(S)-1-phenyl-2-(pyridine-2-base) ethamine free alkali] comprising equal quantities, and namely every kind of dosage comprises (S)-1-phenyl-2-(pyridine-2-base) ethamine of same amount of compound 1 and releasable free alkali form potentially wherein. Therefore as shown in table 3, the modelling Cmax concentration of free alkali compound 1 can directly compare with the different dosing of (S)-1-phenyl-2-(pyridine-2-base) ethamine and (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug.
Table 3
Embodiment 16
This embodiment illustrates when giving prodrug (embodiment 5) and (S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride of (S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride to Canis familiaris L., as shown in by NOEL and LOEL, the risk using prodrug epilepsy is less.
(S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride and vehicle are given via oral tube feed (water) once a day. Preparation prepare weekly twice, once. Store drug-delivery preparation cold preservation in brown glass container (2-8 DEG C) until when needing to be administered. Vehicle is prepared (S)-1-phenyl-2-(pyridine-2-base) ethylamine dihydrochloride of finite concentration scope and then keeps the dose volume (1mL/kg) of all dosage. Independent dosage is based on the nearest body weight for the Canis familiaris L. in this research.
Give every day once to continue 14 days (vehicle is 0.3M gluconic acid pH3.0) with the about the same time (± 1 hour) in every day via oral tube feed by (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug (embodiment 5) as fumarate and vehicle. Vehicle is prepared for (S)-1-phenyl-2-(pyridine-2-base) ethamine of the finite concentration scope prodrug (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug of 30mg/mL (such as 3,10 and) as fumarate, and then keeps dose volume (2mL/kg) for all dosage. Before administration, drug-delivery preparation is warmed to room temperature at least 30 minutes by stirring, and it is continuously stirred to run through whole dosing techniques. Independent dosage is based on the nearest body weight of the Canis familiaris L. used in this study.
Table 4 compound 1 is (S)-1-phenyl-2-(pyridine-2-base) ethamine. After table 4 describes after giving compound 1 dihydrochloride and gives the fumarate prodrug of compound 1, the highest blood level that wherein epilepsy is not shown effect (does not observe action limit, NOEL) the minimum blood level (observing minimum action limit, LOEL) that and wherein epilepsy occurs.In each case, the highest haemoconcentration (Cmax) of free alkali (S)-1-phenyl-2-(pyridine-2-base) ethamine is measured. In the first case, free alkali (S)-1-phenyl-2-(pyridine-2-base) ethamine directly generates from the compound 1 given as dihydrochloride. In the second situation, free alkali (S)-1-phenyl-2-(pyridine-2-base) ethamine generates via the conversion in the body of the prodrug of the compound 1 given as fumarate. (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug given as fumarate is compared with (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug given as dihydrochloride, and the NOEL of epilepsy is higher.
Table 4
* all dosage (in bracket) given reflects free paper mill wastewater.
Embodiment 17
This embodiment illustrates the increase of the dosage of (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug of embodiment 5 in people's intestinal juice, produce the concentration increase of (S)-1-phenyl-2-(pyridine-2-base) ethamine lower than proportional increase level, as seen in figure la and lb. Result, it makes the administration of (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug be difficult to obtain (S)-1-phenyl-2-(pyridine-2-base) ethamine of the relatively direct high concentration giving (S)-1-phenyl-2-(pyridine-2-base) ethamine, and this needs to seek for drug dependence. Without wishing to being bound by theory, wherein first the prodrug of R1 yes (S)-1-phenyl-2-(pyridine-2-base) ethamine is ruptured by DPPIV. There is the endogenous of potential DPPIV and/or external source regulates to affect the prodrug conversion to (S)-1-phenyl-2-(pyridine-2-base) ethamine.
By 20mmol/L (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug solution in DMSO of certain volume (8.25,25,75 and 150 μ L) is added into FaSSIF-v2 (491.75,475,425 and 350 μ L), it is prepared for the stock solution (0.33,1,3 and 6mmol/L) of (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug. Subsequently, the stock solution of 10 μ L (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrugs is added in the supernatant (90 μ LHIF) in vial, mixes 1 minute, and be injected in LC UV system. Hatching the initial concentration of thing is 33,100,300 and 600 μm of ol/L and from hatching sampling in the 5 of beginning, 20,35,65 and 125 minutes. The test of hatching that will use (S)-1-phenyl-2-(pyridine-2-base) ethamine (μm ol/L) is used as standard sample (single-point calibration) to determine synthesis speed and the concentration of (S)-1-phenyl-2-(pyridine-2-base) ethamine. (analytical wavelengths of use is 261nm) is being analyzed with enforcement on the photodiode array detector of WatersAcquityUPLC coupling. The post used is be maintained at 40 DEG C and use 0.2 μ L to connect BEHC-18,1.7 μm of prefilter, 2.1 × 50mmID. The mobile phase used is by 0.03%TFA in A:H2O (v/v) and B: the 0.03%TFA in acetonitrile (v/v) forms. Example gradient: with the flow velocity of 0.6mL/min, initial 1%B be increased to 95%B in 7 minutes and be then maintained at 95%B lasting 0.4 minute. Prodrug to the conversion rate of (S)-1-phenyl-2-(pyridine-2-base) ethamine by the prodrug measured and (S)-1-phenyl-2-(pyridine-2-base) ethamine concentration and time match are determined.
Embodiment 18
Consistent with the observation in vitro from embodiment 17, In vivo study (Examples below 18) in rat describes after the Cmax of (S)-1-phenyl-2-(pyridine-2-base) ethamine as described above is exposed to the transition process between the treatment of (S)-1-phenyl-2-(pyridine-2-base) ethamine prodrug and super therapeutic dose to increase lower than the level being scaling up.These In vivo study results are listed in table 5.
To 52 male and 52 female rats give (a) at vehicle (0.3M gluconic acid, pH3.0) (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug as fumarate in or (b) vehicle (0.3M gluconic acid, pH3.0), give once a day with the about the same time (09:26+/-124 minute) in every day, continue 14. The dosage prodrug of (S)-1-phenyl-2-(pyridine-2-base) ethamine of 300mg/kg (30,100 and) is given with the dose volume of 10mL/kg. After 14 days, within 24 hours, collect blood sample from the lateral tail vein of restricted animal upon administration. 50ul neutrality SarstedtMinivettePOCT capillary tube is used to collect blood sample. Subsequently blood is transferred in the pipe cooled down in advance comprising frost sodium citrate, with hand wobble 5-10 time freezing in dry ice in 10 seconds collected. By whole blood sample on dry ice refrigeration transportation to CovanceLaboratoriesInc. for analysis. Analyze (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug of sample and the concentration of (S)-1-phenyl-2-(pyridine-2-base) ethamine. Whole analytical works are used by CovanceLaboratories, Inc., Madison, Wisconsin to be analyzed method by this development in laboratory the LC/MS/MS that verifies and implements.
Table 5 describes (S)-1-phenyl-2-(pyridine-2-base) the ethamine prodrug that gives treatment and super therapeutic dose to the toxicokinetics parameter after rat.
Table 5
It is orally administered to (S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide fumarate (embodiment 5) average toxicokinetics parameter of (S)-1-phenyl-2-(pyridine-2-base) ethamine in rat after 14 days

Claims (18)

1. the compound or pharmaceutically acceptable salt thereof of formula (I):
Wherein R1 is C1-6Alkyl C (O) O (C1-6Alkoxyl), or
AA is the natural amino acid that peptide bond connects.
2. compound according to claim 1, it is selected from:
Isopropylformic acid. (S)-(1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) methyl ester;
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester;
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester diastereomer 1;
Isopropylformic acid. 2-methyl isophthalic acid-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) propyl ester diastereomer 2;
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester;
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 1;
Acetic acid 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 2;
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester;
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 1;
Isopropylformic acid. 1-((S)-1-phenyl-2-(pyridine-2-base) ethylaminocarbonyl oxygen base) ethyl ester diastereomer 2;
(S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
(S)-1-((S)-2,6-diaminourea caproyl)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
(S)-1-((S)-2-amino-3-(1H-imidazol-4 yl) propiono)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
2-((S)-2-((S)-1-((S)-2-amino-3-(4-hydroxy phenyl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine;
2-((S)-2-((S)-1-((S)-2-amino-3-(1H-indol-3-yl) propiono) pyrrolidine-2-formamido group)-2-phenylethyl) pyridine;
(S)-1-((S)-2-amino-3-PHENYLPROPIONYL)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide; Or
(S)-1-((S)-2-amino-4-methylvaleryl)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide;
Or the pharmaceutical salts of any of the above-described person.
3. compound (S)-1-((S)-2-amino-3-methylbutyryl base)-N-((S)-1-phenyl-2-(pyridine-2-base) ethyl) pyrrolidine-2-Methanamide or its pharmaceutical salts.
4. pharmaceutical composition, it comprises and the compound or pharmaceutically acceptable salt thereof of pharmaceutic adjuvant, the formula (I) as described in claim 1,2 or 3 of diluent or carrier combination.
5. the compound or pharmaceutically acceptable salt thereof of the formula (I) as described in claim 1,2 or 3, it is used for treating.
6. the compound or pharmaceutically acceptable salt thereof of the formula (I) as described in claim 1,2 or 3 is used for the purposes in the medicine for the treatment of depression in preparation.
7. the compound or pharmaceutically acceptable salt thereof of the formula (I) as described in claim 1,2 or 3 is for treating the purposes of depression.
8. the purposes according to claim 6 or 7, wherein said depression is major depressive disorder.
9. the method treating depression, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as described in claim 1,2 or 3 of therapeutically effective amount.
10. method according to claim 9, wherein said depression is major depressive disorder.
11. the compound or pharmaceutically acceptable salt thereof of the formula (I) as described in claim 1,2 or 3 is used for the purposes treating in the medicine of pain in preparation.
12. the compound or pharmaceutically acceptable salt thereof of the formula (I) as described in claim 1,2 or 3 is for treating the purposes of pain.
13. the method for the treatment of pain, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as described in claim 1,2 or 3 of therapeutically effective amount.
14. the compound or pharmaceutically acceptable salt thereof of the formula (I) as described in claim 1,2 or 3 is in the preparation purposes for treating that Rett syndrome, suicidal idea, bipolar disorder, obsessive compulsive disorder, Schain poison gas be poisoning or in the medicine of status epilepticus.
15. the compound or pharmaceutically acceptable salt thereof treatment Rett syndrome of the formula (I) as described in claim 1,2 or 3, suicidal idea, bipolar disorder, obsessive compulsive disorder, Schain poison gas are poisoning or the purposes of status epilepticus.
16. treatment Rett syndrome, suicidal idea, bipolar disorder, obsessive compulsive disorder, Schain poison gas are poisoning or the method for status epilepticus, it compound or pharmaceutically acceptable salt thereof including patient in need gives the formula (I) as described in claim 1,2 or 3 of therapeutically effective amount.
17. compound 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridine or its salt
18. compound 2-((S)-2-phenyl-2-((S)-pyrrolidine-2-formamido group) ethyl) pyridinium dichloride
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